Patent RU-2699034-C1 (RU)
Title: Method of producing compounds of 7h-pyrrolo[2,3-d]pyrimidine
Inventor: STUK TIMOTHY LEE
IPC: C07C309/19
Filed: 2017-02-07
Granted: 2019-09-03
Abstract: FIELD: chemistry. 
     SUBSTANCE: invention relates to versions of an improved novel method of producing compound of 7H-pyrrolo[2,3-d]pyrimidine of formula 1 and a veterinarily acceptable salt thereof. Compound of formula 1 is a JAK inhibitor and can be used in treating diseases associated with JAK activity, such as cancer, asthma, etc. Method comprises a) reacting a compound – trans-4-((methylamino)cyclohexyl)methanesulphonic acid – with 4-substituted 7H-pyrrolo[2,3-d]pyrimidine in water in the presence of a base which is potassium carbonate, lithium, sodium or cesium, at reaction temperature from 60 to 105° with obtaining corresponding salt of trans-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulphonic acid; b) converting the sulphonate salt obtained in step (a) into an intermediate compound which is trans-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulphonyl chloride, in an organic solvent; and c) converting the intermediate compound of sulphonyl chloride obtained in step (b) into a compound of formula 1 by reacting an intermediate compound of sulphonyl chloride with a cold aqueous solution of methylamine, and in case of conversion of compound of formula 1 into its veterinary acceptable salt, reacting compound of formula 1 with corresponding acid in water at 50–65 °C until solid substances have dissolved, crystallization of the product, its separation by filtration, washing and drying. Method variant includes a) reaction of the compound – trans-4-((methylamino)cyclohexyl)methanesulphonic acid with 4-chloro-7H-pyrrolo[2,3-d]pyrimidine and potassium carbonate in water at a temperature of approximately 98 °C for 12 hours to obtain a potassium salt of trans-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulphonic acid, cooling of reagents to about 30 °C, separating solid substances by filtration, washing solid substances with methanol, and drying the solid sulphonate; b) converting the sulphonate obtained in step (a) to intermediate trans-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulphonyl chloride by adding solid sulphonate to an organic solvent , consisting of THF:DIPF (95:5); reagent cooling to approximately 10 °C, adding oxalyl chloride or phosphoryl chloride while maintaining the reaction temperature at about 10 °C, to obtain sulphonyl chloride; c) converting the solid sulphonyl chloride obtained in step (b) into a compound of formula 1 by adding reagents from step (b) to cold aqueous 40 % solution of methylamine, which is at a temperature of about -10 °C; d) adding water and slowly heating the suspension to a boiling point under reflux; distillation of solvent part at 65–75 °C and subsequent slow cooling of reagents to about 35 °C; e) separating solids by filtration and washing solids with water at room temperature, then filtering and drying solid substances, and in case of conversion of compound of formula 1 into its veterinary acceptable salt, reacting compound of formula 1 with corresponding acid in water at 50–65 °C until solid substances have dissolved, product crystallization, its separation by filtration, washing and drying. Invention also relates to a method of producing trans-4-((methylamino)cyclohexyl)methanesulphonic acid (intermediate C) and to novel intermediate compounds selected from 4-((methylamino)phenyl)methanesulphonic acid; trans-4-((methylamino)cyclohexyl)methanesulphonic acid; potassium salt of trans-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulphonic acid; trans-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulphonic acid sodium salt; ((trans)-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulphonyl chloride. 
     EFFECT: disclosed versions of the method of producing a compound of formula 1 using novel intermediate compounds reduce processing time and reduce the cost of the product. 
     15 cl, 4 dwg, 3 tbl, 3 ex